Project IV: Gender, Sex Hormones and Stress-related Smoking (Saladin & Gray) Even with the use of evidence-based treatments, most smokers are unsuccessful when attempting to quit, and cessation rates are particularly discouraging among women. Gender and sex hormone influences on the relationships between stress, craving, and smoking behavior may be key factors underlying this important health disparity. Recent laboratory findings support this assertion, but further work is needed to (a) measure and characterize the relationship between gender/sex hormones and craving experienced by female and male smokers in their real world (i.e., non-laboratory) environment, (b) examine the relationship between gender/sex hormones and stress-induced changes in smoking behavior, and (c) examine the treatment potential of a novel pharmacological agent (oxytocin) that may address gender-relevant stress-responsive smoking behaviors. A mixed naturalistic and laboratory research strategy is proposed to address current gaps in knowledge. Over a two-week period, female and male smokers will provide daily saliva samples for measurement of sex hormones, and will utilize a newly developed and validated software implemented on a personal digital assistant (phone) to provide real-time responses to smoking-related and neutral picture cues presented multiple times daily in their day-to-day natural environment. Participants will then take part in a laboratory session that will examine the effects of oxytocin on stress reactivity and smoking behavior. Prior to the session, participants will abstain from smoking for 12 hours and provide a salivary sample for measurement of stress/sex hormones (Cortisol, estradiol, progesterone, testosterone) levels. Next, participants will receive either oxytocin or placebo and then be exposed to the Trier Social Stress Test (TSST). Measures collected at multiple time points during the laboratory session will include: craving, stress, negative emotion, heart rate, blood pressure, skin conductance, and Cortisol. After the TSST, participants will complete a smoking resistance task (SRT) in which they will receive a monetary reward for every 5-mini period they resist smoking. After the SRT, participants will be allowed to smoke freely during a 1-hour ad libitum smoking period (ASP), with smoking topography assessed via a portable device. It is expected that, in real world settings, females will be more reactive to smoking-related cues than male smokers, and that, among females, the ratio of estradiol to progesterone will be positively related to craving. In the laboratory, it is predicted that (a) females will evidence greater stress, craving, and smoking behavior, but lessneuroendocrine (Cortisol) reactivity, to the TSST, and (b) oxytocin vs. placebo, will attenuate stress, craving, and Cortisol response to the TSST. Findings from the proposed study will substantially address a key gender-related health disparity, potentially informing the development of gender-specific interventions to enhance female smokers' response to cessation treatments. Therefore, the knowledge to be gained may yield significant public health benefits.